刺猬蛋白消耗甾体类CYP17A1拮抗剂：对晚期前列腺癌的潜在治疗意义
Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer.
作者信息
Bordeau Brandon M, Ciulla Daniel A, Callahan Brian P
机构信息
Chemistry Department, State University of New York at Binghamton, 4400 Vestal Parkway East, Binghamton, NY, 13902, USA.
出版信息
ChemMedChem. 2016 Sep 20;11(18):1983-6. doi: 10.1002/cmdc.201600238. Epub 2016 Jul 20.
Abstract
Abiraterone, a potent inhibitor of the human enzyme CYP17A1 (cytochrome P450c17), provides a last line of defense against ectopic androgenesis in advanced prostate cancer. Herein we report an unprecedented off-target interaction between abiraterone and oncogenic hedgehog proteins. Our experiments indicate that abiraterone and its structural congener, galeterone, can replace cholesterol as a substrate in a specialized biosynthetic event of hedgehog proteins, known as cholesterolysis. The off-target reaction generates covalent hedgehog-drug conjugates. Cell-based reporter assays indicate that these conjugates activate hedgehog signaling when present in the low nanomolar range. Because hedgehog signaling is implicated in prostate cancer progression, and abiraterone is administered to treat advanced stages of the disease, this off-target interaction may have therapeutic significance.
摘要
阿比特龙是一种强效的人类酶CYP17A1（细胞色素P450c17）抑制剂，为晚期前列腺癌中异位雄激素生成提供了最后一道防线。在此我们报告了阿比特龙与致癌性刺猬蛋白之间前所未有的脱靶相互作用。我们的实验表明，阿比特龙及其结构类似物加列酮，可以在刺猬蛋白的一种特殊生物合成事件（即胆固醇分解）中替代胆固醇作为底物。这种脱靶反应产生共价的刺猬蛋白 - 药物缀合物。基于细胞的报告基因检测表明，当这些缀合物以低纳摩尔浓度存在时，它们会激活刺猬信号通路。由于刺猬信号通路与前列腺癌进展有关，且阿比特龙用于治疗该疾病的晚期阶段，这种脱靶相互作用可能具有治疗意义。
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